The role of the blood brain barrier in regulating immune surveillance and hemostasis and the deregulation at this site during inflammatory and pro-thrombotic disorders are poorly understood. There is an urgent medical need for improved therapies for diseases such as stroke, cerebral hemorrhage and cerebral thrombotic complications in disorders such as thrombotic thrombocytopenic purpura (TTP), cerebral malaria, meningitis vascular dementia and Alzheimer's Disease (AD) where localized recruitment of activated platelets within the CNS vasculature is a key aspect of the disease process. Antagonists of the platelet alphaIIB-beta3 integrin have been clinically validated for acute coronary syndromes but not thus far for neuro-thrombotic disorders, suggesting that the pivotal interactions regulating thrombotic responses at the blood brain barrier have yet to be defined. [unreadable] Using in vivo phage display, we have identified a novel ligand (TMC-0A3) that targets the brain vasculature with high selectivity and prevents platelet adhesion to brain vasculature under severe inflammatory conditions. Based on our preliminary data, TMC-0A3 is a novel ligand mimetic of the platelet GPIb-alpha that functions as an antagonist of platelet-vWF interactions. In this Phase I application we propose to map the basic pharmacophore structure using the Company's kSAR(TM) technology and optimize the molecule. The optimized molecule will then be used for proof of concept efficacy studies in murine models of arterial thrombosis, cerebral hemorrhage and botrocetin-induced thrombocytopenia to establish whether this mechanism of action can offer an improved therapeutic profile compared to current anti-platelet strategies. [unreadable] This will pave the way for efficacy studies in defined animal models of neuro-thrombotic diseases with the pre-clinical development candidate to support the pre-clinical and phase I clinical development plan that is planned for Phase II of this grant. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]